CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Current lung cancer immunotherapies benefit only a subset of patients.
• Identifying tumor-derived immunosuppressive factors can lead to improved therapeutic strategies.
• Oncogenic driver mutations are early events in lung tumorigenesis.

Purpose of the Study:

• To investigate if driver oncogene expression in lung cancer cells influences cytokine secretion, the immune microenvironment, and tumor progression.
• To determine the role of specific oncogenes like EGFR and KRAS in mediating these effects.
• To explore the potential of targeting identified factors for therapeutic benefit.

Main Methods:

• Analysis of cytokine and chemokine production in lung cancer cells with oncogenic mutations (EGFR, KRAS).
• Utilizing immunocompetent mouse models with syngeneic KRAS-mutant lung cancer cells (wild-type and CCL5-deficient).
• Correlating CCL5 expression with clinical data from lung adenocarcinoma patients, including immune cell populations and patient prognosis.

Main Results:

• Oncogenic EGFR and KRAS mutations induce cytokine and chemokine production, notably CCL5, via MAPK activation.
• KRAS-mutant lung cancer cells lacking CCL5 showed reduced regulatory T cells (Tregs), less T cell exhaustion, and decreased tumor burden in mice.
• High CCL5 expression in lung adenocarcinoma patients correlates with poor prognosis, increased Tregs, and impaired CD8 effector function.

Conclusions:

• Tumor-derived CCL5 promotes an immunosuppressive lung tumor microenvironment, contributing to immunotherapy resistance.
• Targeting CCL5 or its receptors on immunosuppressive cells presents a potential strategy to overcome immunotherapy insensitivity.
• Modulating the tumor microenvironment by targeting CCL5 could enhance lung cancer treatment outcomes.